What this Trial Is About

Clinical Study on the Efficacy and Safety of Methotrexate (MTX) or Thiotepa (for MTX intolerance) or Temozolomide (TMZ) Combined with Orelabrutinib and Selinexor in the Treatment of Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma This study adopts an open-label, prospective, single-arm, single-center design aimed at evaluating the efficacy and safety of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in the treatment of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL). Primary Objective To evaluate the efficacy and safety of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in the treatment of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL). Secondary Objective To assess the benefit-risk balance of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in combination with chemotherapy in the clinical management of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL). Patients with relapsed/refractory primary or secondary CNSL (PCNSL/SCNSL) who meet the inclusion criteria will be enrolled. Previous study data indicate that the combination of orelabrutinib with methotrexate or temozolomide in the treatment of relapsed/refractory central nervous system lymphoma can achieve an ORR of 60%. It is anticipated that the addition of selinexor will increase the ORR to 75%. The treatment effect in r/r CNSL patients is expected to be superior to that of chemotherapy-based combination regimens (one-sided test). With a one-sided alpha = 0.025, beta = 0.1, and an expected enrollment completion within 12 months, along with a follow-up period of 24 months, the planned sample size is 23 patients. Accounting for a 10% dropout rate, the corrected sample size for this study is 25 patients. Patients who meet the inclusion/exclusion criteria and provide signed informed consent will be enrolled in the experimental group. Each treatment cycle lasts 3 weeks. After 6 cycles of induction therapy, patients who do not achieve a PR or experience disease progression at any time will withdraw from the study and receive salvage therapy. Patients who achieve CR or PR will undergo autologous transplantation if they are young and eligible for transplantation. For patients with TP53 mutations, selinexor will be incorporated into the transplant conditioning regimen. Patients who are ineligible for transplantation will receive consolidative radiotherapy. After consolidative therapy, maintenance treatment with orelabrutinib may be administered based on treatment response and patient tolerance. For patients with TP53 mutations, selinexor will be added to orelabrutinib maintenance therapy. For patients with SD/PD, subsequent treatment will be determined by the investigator, followed by observation and follow-up for up to 3 years. Experimental Group Regimen: Induction Therapy: Orelabrutinib 150 mg once daily, selinexor 40 mg weekly, methotrexate 3.5 g/m² (for patients intolerant or resistant to methotrexate: temozolomide 150 mg/m² or thiotepa 30-40 mg/m² may be used as alternatives). Each cycle lasts 3 weeks, for a total of 6 cycles. Maintenance Therapy: Non-TP53mut patients without transplantation: After consolidative radiotherapy, maintenance therapy with orelabrutinib 150 mg once daily may be administered. TP53mut patients without transplantation: After consolidative radiotherapy, maintenance therapy with orelabrutinib 150 mg once daily combined with selinexor 40 mg weekly may be administered.

A Clinical Study on the Efficacy and Safety of Methotrexate (MTX) or Thiotepa (for MTX Intolerance) or Temozolomide (TMZ) Combined With Orelabrutinib and Selinexor in Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma（SELINA）